This invention relates to methods and compositions useful in the therapy of primary open angle glaucoma. Specifically, this invention relates to compositions comprising an aldose reductase inhibitor; and methods of treatment comprising administering these compositions to treat the glaucoma syndrome, a leading cause of blindness.
While applicant is bound by no theory, it appears that an important mechanism underlying open angle glaucoma is one associated with the enzyme aldose reductase and/or related aldehyde reductases. Certain cells of the trabecular meshwork, lamina cribrosa and lamina vasculosa of the eye contain the enzyme aldose reductase and/or related aldehyde reductaces. These reductases under conditions of hyperglycemia or hyperglactosemia cause the accumulation of certain polyols such as sorbitol or galactitol respectively. The inhibition of the enzyme aldose reductase and related reductaces results in the retardation of abnormal polyol accumulation at the expense of NADPH in such ocular cells. Such inhibition preserves normal or near normal reduced glutathione status, Na+/K+ ATPase activity and amino acid transport within said cells. Furthermore, this inhibition promotes or preserves normal collagen production in and around these cells of the trabecular meshwork which are susceptible to high aldose concentrations. This includes cells of the lamina cribrosa and lamina vasculosa in mammalian eyes, particularly those of man. Trabecular meshwork cells are important in preserving proper aqueous humor outflow facility of the eye. Intraocular pressure or tension in part corresponds to outflow facility. In certain conditions of elevated intraocular pressure, the outflow of the trabecular meshwork may be impaired due to abnormal collagen metabolism and insufficient trabecular meshwork cell population. The rheological characteristics of the trabecular meshwork are linked to the normal functions of its cells.
Pathological alterations in collagen production and support in the posterior segments of the eye, which include the lamina cribrosa and lamina vasculosa, are associated with impaired retinal function and vision loss in glaucoma. This weakening of the posterior support structures of the eye is suggested to arise from abnormally elaborated collagen. Aldose reductase inhibitors, such as those disclosed in the present invention, have been demonstrated to prevent an abnormal elaboration of collagen associated with hyperglycemia and/or hypergalactosemia. Hyperglycemia is believed to be associated with the complications of glaucoma in diabetes mellitus patients. It follows that moderate glucose intolerance as is associated with aging may be contributory to glaucoma. Therefore, a potent aldose reductase inhibitor will have therapeutic utility in the therapy and/or prevention of glaucoma.
Thus, it is an object of the present invention to provide methods of treatment and pharmaceutical compositions which will retard or delay the progressive field of vision loss associated with glaucoma; wherein the active in such methods and compositions is an aldose reductase inhibitor.